The efficacy of gait rehabilitations for the treatment of incomplete spinal cord injury: a systematic review and network meta-analysis

Background Recent pieces of evidence about the efficacy of gait rehabilitation for incomplete spinal cord injury remain unclear. We aimed to estimate the treatment effect and find the best gait rehabilitation to regain velocity, distance, and Walking Index Spinal Cord Injury (WISCI) among incomplete spinal cord injury patients. Method PubMed and Scopus databases were searched from inception to October 2022. Randomized controlled trials (RCTs) were included in comparison with any of the following: conventional physical therapy, treadmill, functional electrical stimulation and robotic-assisted gait training, and reported at least one outcome. Two reviewers independently selected the studies and extracted the data. Meta-analysis was performed using random-effects or fixed-effect model according to the heterogeneity. Network meta-analysis (NMA) was indirectly compared with all interventions and reported as pooled unstandardized mean difference (USMD) and 95% confidence interval (CI). Surface under the cumulative ranking curve (SUCRA) was calculated to identify the best intervention. Results We included 17 RCTs (709 participants) with the mean age of 43.9 years. Acute-phase robotic-assisted gait training significantly improved the velocity (USMD 0.1 m/s, 95% CI 0.05, 0.14), distance (USMD 64.75 m, 95% CI 27.24, 102.27), and WISCI (USMD 3.28, 95% CI 0.12, 6.45) compared to conventional physical therapy. In NMA, functional electrical stimulation had the highest probability of being the best intervention for velocity (66.6%, SUCRA 82.1) and distance (39.7%, SUCRA 67.4), followed by treadmill, functional electrical stimulation plus treadmill, robotic-assisted gait training, and conventional physical therapy, respectively. Conclusion Functional electrical stimulation seems to be the best treatment to improve walking velocity and distance for incomplete spinal cord injury patients. However, a large-scale RCT is required to study the adverse events of these interventions. Trial registration: PROSPERO number CRD42019145797. Supplementary Information The online version contains supplementary material available at 10.1186/s13018-022-03459-w.


Introduction
Spinal cord injury temporarily or permanently impairs automatic nervous system, motor, and sensory nerve conduction [1]. Its incidence ranges from 440 to 526 per million population [2]. Levels, types, and extent of injury reflect the muscle strength, spasticity, and gait pattern [3,4]. Gait rehabilitation may help the patients, especially those with incomplete spinal cord injury, to regain their functions and walking ability [5][6][7][8]. Nowadays, widely used gait improvement programs [5,9,10] are hands-on therapy, overground gait training, exercises, and stretching maneuvers. Other potential methods include treadmill; the body-weight-supported treadmill training; functional electrical stimulation; and robotic-assisted gait training. Their possible benefits over conventional physical therapy were neuronal coordination, muscle strength, motor function, balance, walking, and physiologic gait improvement [5,9,11].
The efficacy of various gait rehabilitations has been evaluated. Conventional physical therapy insignificantly enhanced the gait velocity compared to the body-weightsupported treadmill training with or without electrical stimulation [12]. On the other hand, robotic-assisted gait training improved Walking Index of Spinal Cord Injury (WISCI) more than conventional physical therapy and treadmill [11,13]. Evidence is still limited for functional electrical stimulation compared to other methods [14][15][16], particularly robotic-assisted gait training [7,17]. Moreover, there is no comprehensive review of gait training interventions focused on walking ability (i.e., velocity and distance) and safety among incomplete spinal cord injury [11]. A network meta-analysis would be able to demonstrate myriad effects of these interventions.
This systematic review and network meta-analysis of randomized controlled trials (RCTs) aimed to find the best intervention for incomplete spinal cord injury, such as conventional physical therapy, treadmill, functional electrical stimulation, and robotic-assisted gait training. The velocity improvement, distance and functional score of walking as well as safety issues were comprehensively assessed in this study.

Methods
Our systematic review and network meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines extension for network meta-analysis [18]. The study was registered at The International Prospective Register of Systematic Reviews; PROSPERO (ID: CRD42019145797).
One author identified all relevant studies in PubMed and Scopus databases as well as the research works published in academic journals and proceedings and previous systematic reviews with their reference lists up to October 2022. There was no language and status of publication restriction. Search terms comprised spinal cord injury, paralyzed, orthotic, physical therapy, electrical stimulation, treadmill, exoskeleton, robot, gait, velocity, walk and related terms as shown in Additional file 1: Table S1. Two reviewers selected RCTs based on titles and abstracts. If the decision could not be made, full articles were reviewed. Disagreements were resolved by discussion.
Eligible criteria were RCTs involving incomplete spinal cord injury patients with the American Spinal Cord Injury Association (ASIA) Impairment Scale classification grade B, C, and D [19] in comparison with any pairs of the following interventions: conventional physical therapy, functional electrical stimulation, treadmill, and robotic-assisted gait training. We excluded duplicated studies, those with insufficient data for pooling, and inaccessible full-text articles. The study factors were country of recruitment, sample sizes, study subject characteristics (age, time of injury, level of injury, ASIA impairment scale), and duration of interventions. The main outcome represented gait function including velocity (m/s), distance (m), WISCI [20], and WISCI II [21]. The secondary outcomes were any adverse events during gait training such as fall and pressure ulcer. Two reviewers independently retrieved the data using a standardized data extraction form. The quality assessment was separately evaluated by the two reviewers using the revised Cochrane risk-of-bias tool for randomized trials (RoB2) [22]. Each study was classified as having a low, high, or some concern of risk of bias. Any disagreements in data were resolved by team discussion.

Statistical analysis
The direct meta-analysis was performed for each pair of the interventions when there were at least three studies. For continuous outcomes (velocity, distance, and WISCI score), unstandardized mean difference (USMD) with 95% confidence interval (CI) was estimated. The fixed-effects or random-effects model was used according to no or present heterogeneity (Cochrane's Q test p value < 0.1 or Higgins I 2 > 25%), respectively. Sources of heterogeneity were explored by fitting each co-variable (level of injury, duration of injury, ASIA impairment scale, and time of training) in a meta-regression model. An asymmetric funnel plot or p value of the Egger's test less than 0.05 indicated publication bias.
Network meta-analysis was indirectly compared with relative treatment effects across studies. We used linear regression to estimate mean differences for continuous outcomes. Multivariate random-effects meta-analysis with consistency model was performed to pool the relative treatment effects across the studies. Transitivity was indirectly explored by assessing the distribution of the effect of factors (age, gender, ASIA impairment scale, time of injury, and time of training) on the interested outcome between intervention arms. Consistency, agreement between direct and indirect comparisons, was evaluated by a global chi-square test using a design-treatment interaction inconsistency model. In case of significant global chi-square test (p < 0.05), a loop-specific approach was used to identify the treatment arms and studies that mainly contributed to the inconsistency. If inconsistency factors (IF) were greater than or equal to 2, patients' characteristics (i.e., age, level of injury, duration of injury, lesion of injury, and ASIA impairment scale) among treatment arms of the closed loop were explored. A sensitivity analysis was performed by excluding the studies with different characteristics and rechecked the inconsistency assumption with a design-by-treatment interaction model. The probability of being the best intervention was assessed by the probability closest to 100. Surface under the cumulative ranking curve (SUCRA) and rankogram plot were used for ranking treatments [23]. The treatment effect in the future for each treatment regimen was estimated by the predictive interval. Publication bias was checked by using an adjusted funnel plot. All analyses were performed using the STATA software package, version 16.0 (StataCorp, College Station, Texas, USA). The level of significance was < 0.05 for a two-sided p value and < 0.1 for a one-sided p value of heterogeneity test.
The risk-of-bias assessment is shown in Fig. 2. The overall results were of medium quality (29% high [26,29,32,33,37], 59% moderate [17, 24, 25, 27, 28, 34-36, 38, 39], and 12% low quality [30,31]). High-quality studies demonstrated overall low risk of biases. Moderate-quality studies had some concerns about randomization process and/or deviation from the intended intervention, measurement of the outcome, and selection of the reported results, while low-quality studies had a high risk of deviation from the intended intervention and measurement of the outcome.

Discussion
Our systematic review and network meta-analysis evaluated the treatment effects among 5 gait training interventions to improve walking ability of incomplete spinal cord injury patients. Most of the included 17 RCTs were low to some of concerned risks of biases.
From direct meta-analysis, robotic-assisted gait training tended to provide faster walking rate, longer distance, and significantly higher WISCI scores than conventional physical therapy. With regards to the network meta-analysis, there was no significant differences of velocity and distance between gait training interventions. Functional electrical stimulation tended to be the most effective gait training method for both velocity and distance outcomes (probability of being the best treatment 66.6% and 39.7%, respectively) followed by treadmill, functional electrical stimulation + treadmill, robotic-assisted gait training, and conventional physical therapy, respectively.
Robotic-assisted gait training provided better functional level than conventional physical therapy with nonsignificant different speed and distance [13]. Our reviews demonstrated significant 3.3 WISCI score improvement, and subgroup analyses among acute-phase patients with robotic-assisted gait training for at least 2 months significantly increased 0.1 m/s walking rate, and 64.75 m longer distance than the conventional physical therapy. Moreover, subgroup analyses of the level of cervical, thoracic, and lumbar spinal cord injury with robotic-assisted gait training significantly increased 40.45 m longer distance and 2.86 WISCI score than the conventional physical therapy. This might be due to low muscle tone during acute stage. Spasticity usually started 2-6 months after spinal cord injury [40][41][42]. Joint stiffness, muscle shortening [43], and neural plasticity [44,45] would impact functional independence and gait training program [43,46]. The higher the level of spinal cord injury, the more dysfunction of the body, and gait improvement. Either assistant or resistant robotic-assisted gait training could offer advantages in limb control, muscle strengths [47], physiological and reproducible gait patterns [48]. A network meta-analysis by Ma et al. [11] demonstrated that robotic-assisted gait training with overground training improved WISCI score with the highest SUCRA value (88.5) when compared to body weight support treadmill training and body-weight-supported overground training. Additional physical therapy, time of training, and velocity measurement might influence the effects of treatment. However, our subgroup analysis did not find significant difference. According to our network meta-analysis, functional electrical stimulation was preferred to functional electrical stimulation + treadmill and treadmill in terms of velocity and distance without statistically significance.
Functional electrical stimulation can enhance gait, muscle strength, and cardiorespiratory fitness for spinal cord injury patients [49]. Overground training might allow lifting, assisting, and walking variability [50,51]. Field-Fote et al. [17] reported that functional electrical stimulation combined with overground training facilitated walking tasks greater than its combination with body-weight-supported treadmill training. However, including highly impaired participants in functional electrical stimulation + treadmill may cause inferior results [17]. Treadmill alone dominated the effect of walking velocity and distance compared to functional electrical stimulation + treadmill. This method triggers central pattern generators (CPGs) within the spinal cord [52] and improves stride and balance [53], whereas functional electrical stimulation improves foot drop and coordination of the lower limb movement [54][55][56]. Previous research works showed that combined functional electrical stimulation + treadmill could improve velocity and distance more than treadmill [17,54]. Nevertheless, Kesar et al. [54] found nonsignificant difference of percent propulsion of ankle ground reaction force which correlated with velocity [57,58]. This controversy still needs more evidence to support results. Robotic-assisted gait training and conventional physical therapy showed lower velocity and distance improvement than functional electrical stimulation. Even though these three gait rehabilitations build up muscle strengths and balance in spinal cord injury patients [11][12][13], functional electrical stimulation specifically activates weak muscles to improve foot clearance, stride length [59] as well as walking velocity and distance. Moreover, functional electrical stimulation  can alleviate pain and spasticity which might reinforce gait training [60]. Strengths of our study are rigorous methodology as research questions focusing on incomplete spinal cord injury, following PRISMA guidelines, and including recently published RCTs without language restriction. Our search terms covered common gait training interventions and assessed specific outcomes as walking velocity, distance, and WISCI score. We investigated sources of heterogeneity by meta-regression and subgroup analysis and conducted sensitivity analysis by removing the heterogonous studies. Limitations of this review are small number of included studies in some comparison arms leading to imprecise/insignificant estimated treatment effects. Although 88% of included RCTs had low to some concern risk of bias, some of them did not report concealment (selection bias) and were unable to blind outcome assessors (measurement bias). Moreover, weighting methods for risk of biases did not apply for the analysis. The treatment effect of each intervention Table 4 Multiple treatment comparison of the network for velocity and distance     Robotic-assisted gait training significantly improves WISCI score more than conventional physical therapy. Velocity and distance of walking appear to be significant in acute phase of incomplete spinal cord injury patients. However, this gait training is very expensive (40,000-150,000 USD) [61] and requires cheaper price manufacturing with adapted home use. Among the 5 gait trainings, functional electrical stimulation tended to be the most effective intervention to improve velocity and distance of walking. Since functional electrical stimulation had low number of treatment arms and was not included in the direct meta-analysis, only indirect comparisons have been made in the network meta-analysis with nonsignificant difference from other interventions. The interpretation of the final results should be with caution. However, this modality is practical and cost-effective [62,63] and provides good outcomes with affordable price. Further RCTs are recommended to compare robotic-assisted gait training and functional electrical stimulation to achieve a proper conclusion. The revised Cochrane risk-of-bias tool for randomized trials
Additional file 1. Table S1. Search strategy in Medline via PubMed. Table S2. Search strategy in Scopus. Fig. S1. Funnel plots of (a) treadmill (TM) versus conventional physical therapy (CPT) (b) robotic assisted gait training (RAGT) versus conventional physical therapy and (c) contour funnel plot of plot robotic assisted gait training versus conventional physical therapy. Fig. S2. Funnel plots of (a) treadmill (TM) versus convention physical therapy (CPT) (b) robotic assisted gait training (RAGT) versus conventional physical therapy, and contour funnel plot of (c) treadmill versus convention physical therapy and (d) robotic assisted gait training versus conventional physical therapy for distance, Fig. S3.  Fig. S7. Subgroup analysis of time of injury between robotic assisted gait training versus conventional physical therapy on distance of walking (m) in patients with incomplete spinal cord injury. Fig. S8. Subgroup analysis of the level of spinal cord injury between robotic assisted gait training versus conventional physical therapy on distance of walking (m) in patients with incomplete spinal cord injury. Fig. S9. Subgroup analysis of the level of spinal cord injury between robotic assisted gait training versus conventional physical therapy on Walking Index Spinal Cord injury (WISCI) outcome in patients with incomplete spinal cord injury. Fig.  S10. Predictive interval plots of mean difference for velocity (m/s) of 10 pairwise comparisons estimated; values in right column showed mean difference (95% confidence interval) (95% predictive interval). Fig. S11.
Predictive interval plots of mean difference for distance (m) of 10 pairwise comparisons estimated; Values in right column showed mean difference (95% confidence interval) (95% predictive interval).
Author contributions TP, KK, PW, SV, TA, TW, and AT provided substantial contributions to the conception and design of the work; TP, KK, PW, SV, TA, TW, and AT contributed to acquisition, analysis, interpretation of data, and discussion; TP, PW, and TW drafted the work and substantively critiqued and revised the manuscript. All authors have approved the final manuscript.

Funding
None.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.